C-Kit: function and role in normal cells and GISTs

Tyler Downey

KIT Structure

• C-kit encodes KIT, a Cytokine Receptor– Receptor Tyrosine Kinase

(RTK)

• KIT Ligand – Stem Cell Factor (SCF)

D. Linnekin / The International Journal of Biochemistry & Cell Biology

KIT Activation

• Homodimerization

• Increased auto-phosphorylation

• Kinase domain activation

Heinrich et al, Human Pathology Volume 33, No. 5 (May 2002)

Kit Molecular Pathways

- Pathways Activated:• Src Family• Ras• PI-3 Kinase Family• JAK/STAT Family-KIT Inhibition Pathways:• SHP1 & SHP2

D. Linnekin / The International Journal of Biochemistry & Cell Biology

Where is KIT expressed?LacZ mice

• Mice embryos express WLacZ mutation on c-kit• Breed WLacZ/WLacZ and WLacZ/+ mice and look for

β-gal-positive cells

F. Bernex et al Development 122, 3023-3033 (1996)

2 forms of KIT expression in embryogenesis

• KIT expressed but not essential for survival/proliferation/migration

• Endothelial cells, endocrine cells, Interstitial cells of cajal (ICC)

• KIT expression essential for survival/proliferation/migration

• Melanoblasts, Primordial Germ Cells (PGC), hematopoietic progenitors

Cellular Responses to KIT

• Survival• Proliferation• Migration• Differentiation• Adhesion

•main forms of KIT function:

- c-kit function essential during

embryogenesis

- c-kit function essential in post-natal

tissues

KIT in Cancer

• Gastrointestinal Stromal Tumors (GISTs)– Most common mesenchymal tumors of digestive

tract.– Constitutively activated KIT mutants found in over

90% of GISTs– GISTs form from Interstitial Cells of Cajal (ICC)

• Expresses c-kit and CD34, same as GIST tumors

• Kit expression also found in seminomas, and leukemia

Interstitial Cells of Cajal (ICC)

• Pacemakers of intestine– Cause smooth muscle

contraction of the intestine• ICC precursors require c-kit for

differentiation• Only cell type in intestine to

normally express c-kit and CD34– C-kit and CD34 both expressed

in GIST

T. Komuro J Physiol 576.3 (2006)

C-kit Role in GIST

• Early KIT oncogenic expression pivotal in GIST tumorigenesis

• KIT mutation alone causes ICC hyperplasia

• Chromosome deletions follow KIT mutation

Forms of KIT mutation• 2 forms of KIT mutation

– Mutation of regulatory region of KIT• Most common in juxtamembrane region of KIT

– Mutation of Kinase region of KIT

• Some constitutively activated KITs may have altered signaling pathway

Heinrich et al, Human Pathology Volume 33, No. 5 (May 2002)